The present invention relates to novel 2-phenylbenzimidazoles and 2-phenylindoles, their preparation and their use as inhibitors of the enzyme poly(ADP-ribose)polymerase or PARP (EC 2.4.2.30) for the production of drugs.
Poly(ADP-ribose)polymerase (PARP) or poly(ADP-ribose)synthase (PARS), as it is also known, is a regulatory enzyme which is found in cell nuclei (K. Ikai et al., J. Histochem. Cytochem. 1983, 31, 1261-1264). It is assumed that PARP plays a part in the repair of DNA bridges (M. S. Satoh et al., Nature 1992, 356, 356-358). Damage to or breaks in the DNA strands activate the enzyme PARP which, when it is activated, catalyzes the conversion of ADP-ribose from NAD (S. Shaw, Adv. Radiat. Biol., 1984, 11, 1-69). During the course of this, nicotinamide is released from NAD. Nicotinamide is converted into NAD again with consumption of the energy carrier ATP of other enzymes. Overactivation of PARP would accordingly have resulted in an unphysiologically high consumption of ATP and this leads, in extreme cases, to cell damage and cell death.
It is known that free radicals such as the superoxide anion, NO and hydrogen peroxide can lead to DNA damage in cells and thus activate PARP. The formation of large amounts of free radicals is observed in a number of pathophysiological conditions and it is assumed from this that this accumulation of free radicals leads or contributes to the observed cell and organ damage. This includes, for example, ischemic conditions of organs such as in stroke, cardiac infarct (C. Thiemermann et al., Proc. Natl. Acad. Sci. USA, 1997, 94, 679-683) or ischemia of the kidneys, but also reperfusion damage such as occurs, for example, after lysis of cardiac infarct (see above: C. Thiemermann et al.). The inhibition of the enzyme PARP could accordingly be a means of preventing or alleviating this damage at least partly. PARP inhibitors could thus be a new therapeutic principle for the treatment of a number of diseases.
The enzyme PARP affects the repair of DNA damage and could thus also play a part in the therapy of carcinomatous disorders, since in combination with cytostatically active substances a higher potential of action against tumor tissue was observed (G. Chen et al. Cancer Chemo. Pharmacol. 1988, 22, 303).
Nonlimiting examples of tumors are leukemia, glioblastoma, lymphoma, melanoma, mastocarcinoma and cervical carcinoma.
Moreover, it has been found that PARP inhibitors can show immunosuppressant action (D. Weltin et al. Int. J. Immunopharmacol. 1995, 17, 265-271).
It was also discovered that PARP is involved in immunological disorders or diseases in which the immune system plays an important part, such as, for example, rheumatoid arthritis and septic shock, and that PARP inhibitors can show a favorable effect on the course of the disease (H. Krxc3x6ger et al. Inflammation 1996, 20, 203-215; W. Ehrlich et al. Rheumatol. Int. 1995, 15, 171-172; C. Szabo et al., Proc. Natl. Acad. Sci. USA 1998, 95, 3867-3872; S. Cuzzocrea et al. Eur. J. Pharmacol. 1998, 342, 67-76).
Within the meaning of this invention, PARP is understood as also meaning isoenzymes of the above-described PARP enzyme.
Furthermore, the PARP inhibitor 3-aminobenzamide showed protective effects in a model for circulatory shock (S. Cuzzocrea et al., Br. J. Pharmacol. 1997, 121, 1065-1074).
There are likewise experimental indications that inhibitors of the enzyme PARP could be useful as an agent for the treatment of diabetes mellitus (V. Burkart et al. Nature Med. 1999, 5, 314-319).
2-Phenylbenzimidazoles have been widely described. Thus, in DE 38 30 060 alkylated derivatives are disclosed as inhibitors of erythrocyte aggregation. In DE 35 22 230, an ester derivative of 2-phenylbenzimidazole is mentioned as an inhibitor of platelet aggregation. Halogen-substituted 2-phenylbenzimidazoles which carry substituted amine radicals on the phenyl ring have been described as MCP-1 antagonists in WO 98/06703.
2-Phenylbenzimidazoles are also known in which the benzimidazole group is substituted by an amide group. 5-Amido derivatives of 2-phenylbenzimidazole, which carry alkyloxy radicals on the phenyl ring, have been described as inhibitors of cAMP phosphodiesterase in WO 94/12461. For analogous derivatives, it was found in DE 35 46 575 (e.g. Example 15) that these compounds induce positively inotropic effects. 4-Amido derivatives which carry a pyridyl radical in the 3-position are also described as inhibitors of cAMP phosphodiesterase in WO 97/48697.
The synthesis of 2-phenylbenzimidazyl-4-amides has been described in J. Chem. Soc. Perkin Trans 1, 1979, 2303-2307. Analogous compounds which carry a further substituted alkyl chain on the amide radical, and which are said to have cytotoxic action, are mentioned in J. Med. Chem. 1990, 33, 814-819. In WO 97/04771, however, benzimidazole-4-amides which inhibit PARS are mentioned. In particular, derivatives which carry a phenyl ring in the 2-position are described as active there, it additionally being possible to substitute the phenyl ring with simple substituents such as nitro, methoxy and CF3. Although these substances in some cases show good inhibition of the enzyme PARP, the derivatives described there have the disadvantage that they only show little or no solubility in aqueous solutions and thus cannot be administered as an aqueous solution.
In a number of therapies such as stroke, the active compounds are administered intravenously as an infusion solution. To this end, it is necessary to have available substances, in this case PARP inhibitors, which have sufficient water solubility at physiological pHs or approximate pHs (e.g.: pHs of 5-8) so that an infusion solution can be prepared. Many of the described PARP inhibitors, in particular the better active PARP inhibitors, have the disadvantage, however, that they only show low or no water solubility at these pHs and are thus not suitable for intravenous administration. Active compounds of this type can only be administered with auxiliaries which are intended to mediate the water solubility (cf. WO 97/04771). These auxiliaries, for example polyethylene glycol and dimethyl sulfoxide, often cause side effects or are even intolerable. Highly efficacious PARP inhibitors having adequate water solubility have not been described until now.
It has surprisingly been found that 2-phenylbenzimidazoles which additionally carry an amine radical on the phenyl ring are highly efficacious inhibitors which, however, make possible salt formation with acids due to the incorporation of the aliphatic amine radical and as a result show a markedly improved water solubility.
In the present invention, novel 2-phenylbenzimidazole and 2-phenylindole derivatives of the general formula I are described which, compared with the compounds already described, show advantages and are potent PARP inhibitors and at the same time also show adequate water solubility, which makes possible administration as an infusion solution.
The present invention relates to substituted 2-phenylbenzimidazoles and 2-phenylindoles of the general formula I: 
in which
A is N or CH,
R1 is hydrogen, branched or unbranched C1-C6-alkyl, where one C atom of the alkyl radical can further carry OR11, where
R11 is hydrogen or C1-C4-alkyl, and
R2 is hydrogen, chlorine, fluorine, bromine, iodine, branched or unbranched C1-C6-alkyl, nitro, CF3, CN, NR21R22, NHxe2x80x94COxe2x80x94R23, OR21, where
R21 and R22 independently of one another are hydrogen or C1-C4-alkyl and
R23 is hydrogen, C1-C4-alkyl or phenyl, and
R3 is xe2x80x94(CH2)qxe2x80x94NR31R32, (CH2)qxe2x80x94NR33R34, where q can be 0, 1, 2 or 3
R31 is hydrogen, C1-C6-alkyl, (CH2)4NR33R34,
R32 is (CH2)rNR33R34, in which, if R31 and R32 are independent of one another, r is 2, 3, 4, 5 or 6 and R33 and R34 independently of one another are hydrogen, C1-C6-alkyl, together with the nitrogen atom are a ring of 3 to 8 atoms which can carry an additional heteroatom selected from O, Nxe2x80x94C1-C4-alkyl, Nxe2x80x94C0-C2-phenyl or NH, phenyl-C1-C4-alkyl, where the phenyl ring can be substituted by up to 3 identical or different subtituents selected from the group consisting of C1-C6-alkyl, halogen, nitro, SO2NR35R36 (where R35, R36 independently of one another are hydrogen, C1-C4-alkyl or together with the nitrogen are a ring of 3 to 8 atoms which can carry an additional hetero atom selected from O, S, SO2, Nxe2x80x94C1-C4-alkyl, Nxe2x80x94C0xe2x80x94C2-phenyl or NH), C1-C4-alkoxy, S(O)0-2xe2x80x94R37 (where R37 is hydrogen, C1-C4-alkyl), CF3, (CH2)0-4xe2x80x94COR37, (CH2)0-4NR35R36, (CH2)0-4CONR35R36, (CH2)0-4OR37xe2x80x94CH2COOR37,
R4 is hydrogen, branched or unbranched C1-C6-alkyl, chlorine, bromine, fluorine, nitro, cyano, NR41R42, NHxe2x80x94COxe2x80x94R43, OR41, where
R41 and R42 independently of one another are hydrogen or C1-C4-alkyl and
R43 is C1-C4-alkyl or phenyl.
Preferred positions for the radical R2 in the general formula I are the 3-position and the 4-position relative to the benzimidazole ring. For the radical R3, the 3-position or 4-position relative to the benzimidazole ring is likewise preferred.
The preferred meaning of A is nitrogen.
The preferred meaning of R1 is hydrogen.
The preferred meaning of R2 is hydrogen, branched or unbranched C1-C6-alkyl, nitro, CN, NH2, Oxe2x80x94C1-C4-alkyl. R2 is particularly preferably hydrogen.
The preferred meaning of R3 is (CH2)1-2xe2x80x94NR33R34 and N(R31)xe2x80x94(CH2)2-3xe2x80x94NR33R34, in which R31 is hydrogen or C1-C4-alkyl, R33 and R34 independently of one another are hydrogen or C1-C4-alkyl, or the group NR33R34 represents a radical selected from the group consisting of piperidine, pyrrolidine, azepine and piperazine, where the piperazine on the second N is substituted by hydrogen or Cl-C4-alkyl.
The preferred meaning of R4 is hydrogen.
The respective combinations of the above preferred meanings are very particularly preferred.
The compounds of the formula I can be employed as racemates, as enantiomerically pure compounds or as diastereomers. If enantiomerically pure compounds are desired, these can be obtained, for example, by carrying out a classical resolution with the compounds of the formula I or their intermediates using a suitable optically active base or acid.
The invention also relates to compounds which are mesomeric or tautomeric to compounds of the formula I.
The invention further relates to the physiologically tolerable salts of the compounds I which can be obtained by reaction of compounds I with a suitable acid or base. Suitable acids and bases are listed, for example, in Fortschritte der Arzneimittelforschung, 1966, Birkhxc3xa4user Verlag, Vol. 10, pp. 224-285. These include, for example, hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid etc., and sodium hydroxide, lithium hydroxide, potassium hydroxide and tris.
Prodrugs are understood as meaning those compounds which are metabolized to compounds of the general formula I in vivo. Typical produgs are phosphates, carbamates of amino acids, esters and others.
The preparation of the substances I according to the invention can be carried out in various ways, which are analogous to those which have been outlined in WO 98/06703 for benzimidazole and indole, and Synthesis Schemes 1-3. 
The benzimidazole VII is obtained by condensation of the benzaldehyde with phenylenediamines, the reaction preferably being carried out in polar solvents such as ethanol or dimethylformamide and with addition of acids such as acetic acid at. elevated temperature, as a rule 80-120xc2x0 C. The addition of weak oxidants such as copper(II) salts, which are added as an aqueous solution, is favorable for the reaction. 
If R=NH2 in the phenylenediamine VII, compounds I according to the invention are formed directly in the condensation. Otherwise, if R=O-alkyl, this ester can be reacted with ammonia, if appropriate at elevated temperature and elevated pressure, to give the amide I. Alternatively, the ester VII can be reacted with hydrazine in polar solvents such as the alcohols butanol and ethanol or alternatively dimethylformamide, at elevated temperatures, preferably 80-130xc2x0 C., a hydrazide VII (R=NHNH2) being obtained which can then additionally be reduced under reductive conditions, such as with Raney nickel in alcohols under reflux, to give the amide I.
Introduction of the radical R1 into the benzimidazole radical in I (R1=H) takes place under alkylating conditions as above (see V-VI), where, however, the reaction component R1xe2x80x94L (L=leaving group as above) has to be employed (see Scheme 1). 
Alternatively to the benzaldehydes VI shown in Scheme 1, benzoic acids such as XI (see Scheme 2) or benzonitriles such as XIV (see Scheme 3) can be employed instead of the benzaldehyde. The preparation of these derivatives is carried out analogously to the preparation of the substituted benzaldehydes V. Starting from XI, the condensation to give VII is carried out in two stages. First, the benzoic acid XI is reacted with the aniline VI in a peptide-like coupling to give the amide XII. The reaction here is carried out according to customary conditions, which are listed, for example, in Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), 4th Ed., E5, Chap. V or C. R. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 972 ff. The ring closure to give the benzimidazole is then carried out at elevated temperature, for example 60-180xc2x0 C., with or without solvents such as dimethylformamide, with addition of acids such as acetic acid or directly in acetic acid itself.
The reaction of the phenylenediamine VII with a benzonitrile XIV is likewise carried out under customary conditions. The reaction can in this case be carried out in solvents such. as dimethylformamide with addition of acids or also in polyphosphonic acid at elevated temperature such as 60-200xc2x0 C. However, the customary methods for the preparation of amidines from benzonitriles can also be used, such as are described in Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), E5, p.1304 f., J. Amer. Chem. Soc. 1957, 427 and J. Org. Chem. 1987, 1017.
The substituted 2-phenylbenzimidazoles and 2-phenylindoles I contained in the present invention are inhibitors of the enzyme poly(ADP-ribose)polymerase or PARP (EC 2.4.2.30).
The inhibitory action of the substituted 2-phenylbenzimidazoles and 2-phenylindoles I was determined using an enzyme test already known in the literature, a Ki value being determined as an activity standard. The 2-phenylbenzimidazoles and 2-phenylindoles I were measured in this manner for inhibitory action of the enzyme poly(ADP-ribose)polymerase or PARP (EC 2.4.2.30).
The substituted 2-phenylbenzimidazoles and 2-phenylindoles of the general formula I are inhibitors of poly(ADP-ribose)polymerase (PARP) or poly(ADP-ribose)synthase (PARS) as it is also called and can thus be used for the treatment and prophylaxis of diseases which are associated with an increased enzyme activity of these enzymes.
The compounds of the formula I can be employed for the production of drugs for the treatment of damage after ischemia and for prophylaxis in the case of expected ischemias of various organs.
The present 2-phenylbenzimidazoles and 2-phenylindoles of the general formula I can accordingly be used for the treatment and prophylaxis of neurodegenerative diseases which occur after ischemia, trauma (craniocerebral trauma), mass hemorrhages, subarachnoid hemorrhages and stroke, and of neurodegenerative diseases such as multiple infarct dementia, Alzheimer""s disease, Huntington""s disease and of epilepsies, in particular of generalized epileptic attacks, such as, for example, petit mal and tonic-clonic attacks and partial epileptic attacks, such as temporal lobe and complex partial attacks, and furthermore for the treatment and prophylaxis of damage to the heart after cardiac ischemia and damage to the kidneys after renal ischemia, for example of acute renal insufficiency, of acute kidney failure or of damage which occurs during and after a kidney transplant. The compounds of the general formula I can furthermore be used for the treatment of acute myocardial infarct and damage which occurs during and after medicinal lysis thereof (for example with TPA, reteplase, streptokinase or mechanically with a laser or Rotablator) and of microinfarcts during and after heart valve replacement, aneurysm resections and heart transplants. The present 2-phenylbenzimidazoles and 2-phenylindoles I can likewise be used for the treatment of revascularization of critically constricted coronary arteries, for example in PCTA and bypass operations, and critically constricted peripheral arteries, for example leg arteries. Moreover, the 2-phenylbenzimidazoles and 2-phenylindoles I can be beneficial in the chemotherapy of tumors and metastasis thereof and can be used for the treatment of inflammation and rheumatic disorders, such as, for example, rheumatoid arthritis.
In addition to the customary pharmaceutical auxiliaries, the pharmaceutical preparations according to the invention contain a therapeutically efficacious amount of the compounds I.
For local external application, for example in powders, ointments or sprays, the active compounds can be contained in the customary concentrations. As a rule, the active compounds are contained in an amount of 0.001 to 1% by weight, preferably 0.001 to 0.1% by weight.
In the case of internal administration, the preparations are administered in individual doses. In an individual dose, 0.1 to 100 mg are provided per kg of body weight. The preparations can be administered daily in one or more doses depending on the nature and severity of the disorders.
According to the type of administration desired, the pharmaceutical preparations according to the invention contain the customary carriers and diluents in addition to the active compound. For local external application, industrial pharmaceutical auxiliaries, such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, paraffin oil, petroleum jelly and wool fat can be used. For internal administration, for example, lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone are suitable.
Antioxidants such as tocopherol and butylated hydroxyanisole and also butylated hydroxytoluene, flavor-enhancing additives, stabilizers, emulsifiers and lubricants can furthermore be contained.
The substances contained in addition to the active compound in the preparation and the substances used in the production of pharmaceutical preparations are toxicologically acceptable and compatible with the respective active compound. The production of the pharmaceutical preparations is carried out in a customary manner, for example by mixing the active compound with other customary carriers and diluents.
The pharmaceutical preparations can be administered in various manners of administration, for example orally, parenterally, such as intravenously by infusion, subcutaneously, intraperitoneally and topically. Thus preparation forms such as tablets, emulsions, infusion and injection solutions, pastes, ointments, gels, creams, lotions, powders and sprays are possible.